A comprehensive understanding of the mechanisms associated with the generation and modulation of immunological T cell memory will lead to a better understanding of how the immune system controls viral infections but also causes immune-mediated pathology. Heterologous immunity occurring as a consequence of T cell cross-reactivity (XR) between unrelated pathogens, such as influenza A (IAV), vaccinia virus, arenaviruses, and murine cytomegalovirus, has been shown by us with animal models to contribute to reduced (beneficial) or enhanced viral loads, and remarkably altered immunopathology (detrimental). We have demonstrated heterologous immunity in human infections with Epstein-Barr virus (EBV), while other investigators have demonstrated its role in influenza, dengue, and hepatitis C viruses. We have identified networks of cross-reactive T cells, which interact with EBV-BMLF1 280 in HLA-A2+ patients with acute infectious mononucleosis (AIM) and directly correlated the severity of AIM with the frequency of memory influenza A M158-specific CD8 T cells cross-reactive with EBV-epitopes. The cross-reactive repertoire appears broader than the non-cross-reactive repertoire to either antigen alone. We have evidence in five EBV-seronegative healthy donors that a unique cross-reactivity between IAV M1-specific responses and EBV epitopes maybe protective. The overall objective of this proposal is to determine how T cell cross-reactivity impacts T cell selection and function, and changes disease outcome, to the worse or better, as the host is exposed to subsequent acute or persistent infections such as EBV. Insights on these issues are necessary for the intelligent design of modern vaccines that are effective and without unwanted side effects and to develop therapeutic interventions when virus infection induces immunopathology. We are one of the few groups studying heterologous immunity in viral systems and propose to clarify these issues in the following aims: 1) examine the mechanisms which control the balance between protective immunity versus pathology in heterologous immunity during EBV infection; 2) examine how XR TcR repertoires influence heterologous protective immunity and immunopathology; 3) test the hypothesis that elderly individuals have increased crossreactive responses due to heterologous infections.